EP0200591B1 - Verfahren zur Herstellung von reinen Androst-2-enderivaten - Google Patents

Verfahren zur Herstellung von reinen Androst-2-enderivaten Download PDF

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Publication number
EP0200591B1
EP0200591B1 EP86400622A EP86400622A EP0200591B1 EP 0200591 B1 EP0200591 B1 EP 0200591B1 EP 86400622 A EP86400622 A EP 86400622A EP 86400622 A EP86400622 A EP 86400622A EP 0200591 B1 EP0200591 B1 EP 0200591B1
Authority
EP
European Patent Office
Prior art keywords
radical
androstene
pure
isomer
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP86400622A
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English (en)
French (fr)
Other versions
EP0200591A1 (de
Inventor
Robert Grignard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoire Theramex SAM
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Laboratoire Theramex SAM
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoire Theramex SAM filed Critical Laboratoire Theramex SAM
Priority to AT86400622T priority Critical patent/ATE40139T1/de
Publication of EP0200591A1 publication Critical patent/EP0200591A1/de
Application granted granted Critical
Publication of EP0200591B1 publication Critical patent/EP0200591B1/de
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/003—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring the S atom directly linked to a ring carbon atom of the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3

Definitions

  • a process for obtaining an androstenic compound A-2 in the pure state from a mixture of A-2 (3) and A-3 (4) androstene characterized in that a mixture is subjected androstenes corresponding to the general formula in which the dotted line symbolizes a double bond in position 2 (3) or in position 3 (4)
  • R represents a free hydroxyl, esterified by an organic acid having from 1 to 10 carbon atoms, or etherified by an alkyl or tetrahydro-pyranyl radical
  • R ' represents hydrogen, a lower alkenyl radical, a lower alkynyl radical, a radical lower alkyl, a phenyl radical or a cycloalkyl radical or R and R 'together form the oxygen of a ketone function
  • the wavy line indicates an a or 13 orientation to the action of a pure sulfonating agent or in an inert solvent in the possible presence of a dehydrating agent to obtain an A-3 androsenyl 2-s
  • the present invention is based on the surprising observation that it is possible to sulfonate selectively in anhydrous medium the androstenic isomer A-3 in order to obtain a strongly acid derivative of water-soluble, corresponding to the general formula II wherein the substituents R and R 'have the meanings previously provided.
  • This derivative is then easily eliminated by anion exchange resins in an alcoholic medium or simply by pouring the reaction medium into water, an operation which causes the insoluble, unconverted steroid A-2 to crystallize, and to dissolve the sulfonated steroid A-3. After filtration, washing with water and drying, the pure steroid A-2 is obtained.
  • Sulfonation with sulfuric acid, pure or in solution is carried out in an inert solvent such as, for example, acetic acid, dichloromethane, chloroform, dioxane, in the presence of a dehydrating agent such as anhydride d alkylcarboxylic acid such as acetic anhydride or propionic anhydride.
  • the temperature of the reaction medium can vary from 5 ° C. to + 50 ° C. This reaction time, from a few minutes to several days, depending on the operating conditions.
  • the structural analysis of the purified steroid was carried out by infrared spectrophotometry and by nuclear magnetic resonance of the proton.
  • the olefinic protons in C2 and C3 appear in the form of a singlet widened to 334 Hz (half-width 5 Hz) while for the A-3 androstenic derivatives, the olefinic protons appear in the form of 4 masses between 312 and 348 Hz.
  • the invention also relates to the A-3-androstenyl-2-sulfonic acids of general formula II, formed during the execution of the process according to the invention.
  • the reaction medium was poured quickly into 300 ml of anhydrous ethanol, and after 2 hours of stirring, the solution obtained was passed through a column loaded with 50 g of anion exchange resin, DOWEX® AG2 X8 (in the form OH-) previously dehydrated with anhydrous ethanol. After passing the solution, the column was washed with 100 ml of ethanol, the combined effluents and washing liquors were evaporated to dryness under vacuum.
  • anion exchange resin DOWEX® AG2 X8 (in OH- form), previously dehydrated with methanol and 30 minutes at room temperature, were added. It is filtered, the resin is washed with 50 ml of methanol and the filtrate and the combined washing liquids are evaporated to dryness.
  • the A-2 androstenic derivatives of general formula IV are drugs which behave, according to the conditions of use, as brakers or on the contrary pituitary stimulants.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (8)

1. Verfahren für die Herstellung einer A-2 Androstenischen Verbindung im reinen Zustand von einem Gemisch von A-2(3) und A-3(4) Androstenen dadurch gekennzeichnet dass ein Gemisch von Androsten der allgemeinen Formel
Figure imgb0009
in der
die punktierte Linie eine Doppel Bindung in Stellung 2(3) oder 3(4) bedeutet
R für eine freie, mit einer organische C1-C10 Säure esterifierte oder mit einem Alkyl Radikal oder einem Tetrahydropyranyl etherifierte Hydroxyl steht R' Wasserstoff, ein niedrig Alkenyl Radikal, ein niedrig Alkynyl Radikal, ein niedrig Alkyl Radikal, ein Phenyl Radikal ist
oder R und R' zusammen das Sauerstoff einer ketonische Funktion bilden
und die wellenförmige Linie eine a oder β räumliche Orientierung bedeutet
auf die Wirkung eines reinen oder in einem inerten Lösungsmittel Sulfonierungsmittel gegebenenfalls in Anwesenheit eines Dehydratisierungsmittel unterworfen wird, um eine A-3 Androstenyl 2-sulfonsäure der allgemeinen Formel ll
Figure imgb0010
zu erlangen und die reine, unverwandelte A-2(3) androstenische Verbindung der allgemeinen Formel IV
Figure imgb0011
worin die substituenten R und R' die selbe Bedeutungen wie vorher, besitzen zuruckgewonnen wird.
2. Verfahren zur Herstellung nach Anspruch 1, worin der Sulfonierungsmittel, Schwefelsäure ist.
3. Verfahren zur Herstellung nach Anspruch 2, worin das inertes Lösungsmittel für die Sulfonierungsumsetzung aus der Gruppe von einer aliphatischen Säure, eines Halogen-haltigen kohlenwasserstoff eines cyclischen Äther und eines linearen Äther gewählt ist.
4. Verfahren zur Herstellung nach Anspruch 2, worin die Sulfonierung in Anwesenheit eines Dehydrierungsmittel durchgeführt wird.
5. Verfahren zur Herstellung nach Anspruch 2, worin die Abtrennung der A-3 Androstenyl-2-sulfonsäure durch Zugabe eines wässerigen Mediums das sie auflöst, durchgeführt ist.
6. Verfahren zur Herstellung nach Anspruch 2, worin die A-3 Androstenyl-2-sulfonsäure durch auf einem Anionvertauscher Harz Durchgang, isoliert wird.
7. Verfahren zur Herstellung nach Anspruch 2, worin das Dehydrierungsmittel, das Anhydrid einer Alkyl carbonsäure wie Essigsäure Anhydrid oder Propionsäure Anhydrid, ist.
8. Die A-3 Androstenyl-2-sulfonsäure der allgemeinen Formel 11
Figure imgb0012
worin die substituenten R und R' die vorherige angegebene Bedeutungen haben, und die wellenförmige Linie eine a oder β räumliche Orientierung bedeutet.
EP86400622A 1985-04-29 1986-03-25 Verfahren zur Herstellung von reinen Androst-2-enderivaten Expired EP0200591B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT86400622T ATE40139T1 (de) 1985-04-29 1986-03-25 Verfahren zur herstellung von reinen androst-2enderivaten.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8506471 1985-04-29
FR8506471 1985-04-29

Publications (2)

Publication Number Publication Date
EP0200591A1 EP0200591A1 (de) 1986-11-05
EP0200591B1 true EP0200591B1 (de) 1989-01-18

Family

ID=9318768

Family Applications (1)

Application Number Title Priority Date Filing Date
EP86400622A Expired EP0200591B1 (de) 1985-04-29 1986-03-25 Verfahren zur Herstellung von reinen Androst-2-enderivaten

Country Status (3)

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EP (1) EP0200591B1 (de)
AT (1) ATE40139T1 (de)
DE (1) DE3661832D1 (de)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3098851A (en) * 1961-11-20 1963-07-23 Searle & Co 17alpha-alkynyl-2beta-halo-5alpha-androstane-3alpha, 17beta-diols, esters thereof, and intermediates thereto
GB1492746A (en) * 1974-01-17 1977-11-23 Theramex Androstane derivatives and compositions containing them
ATE19781T1 (de) * 1981-06-02 1986-05-15 Theramex Androstenen enthaltenden pharmazeutische zusammensetzungen.

Also Published As

Publication number Publication date
EP0200591A1 (de) 1986-11-05
ATE40139T1 (de) 1989-02-15
DE3661832D1 (en) 1989-02-23

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